Rheumatoid arthritis (RA) is a highly disabling autoimmune disease with reduced survival that disproportionately affects women 3 to 4 times more frequently than men. Clinical, epidemiological and animal studies suggest a role and potential interaction between genetic factors, sex steroid hormones, and inflammatory cytokines on risk of RA, but these interrelationships are poorly understood. The overall goal of this study is to define the contribution of serum hormones, inflammatory markers and genetic factors in the etiology of RA in women using a prospective nested case-control design. The proposed study uses 3 ongoing cohorts, the Nurses' Health Study (NHS), the Nurses' Health Study II (NHS II), and the Women's Health Study (WHS). Blood samples were collected and archived since 1989 from 90,572 cohort participants. The study will be almost three times larger than the next largest prospective study. We will use a validated method to ascertain RA cases; we expect to confirm 1200 incident cases overall and will have archived blood samples available for 500 cases. Specifically, we hypothesize that low plasma total and free testosterone, low DHEAS, and low levels of prolactin are positively associated with subsequent risk of RA among women and men. Similarly, elevated levels of C-reactive protein (CRP) and interleukin-6 (IL-6) are prospectively associated with increased risk. We will also examine the association of genetic polymorphisms in the progesterone, estrogen, and androgen and receptors, as well as the association of polymorphisms in corticotrophin releasing hormone, CYP19, and tumor necrosis factor genes with risk of RA. The large size (>500 RA cases) and prospective nature of the proposed study, along with the availability of archived blood samples and data on other RA risk factors, provides a unique opportunity to further our understanding of the etiology of RA in women. Ultimately, this study could lead to the identification of potential targets for therapeutic interventions to treat RA or to reduce the risk of this serious autoimmune disease.